Reelin-LRP8 signaling mediates brain dissemination of breast cancer cells via abluminal migration

Reelin-LRP8 signaling mediates brain dissemination of breast cancer cells via abluminal migration

Abstract Brain metastasis (BM) remains a significant challenge in breast cancer (BC) management. While conventional metastatic routes primarily involve hematogenous dissemination, emerging evidence suggests that BC cells can also migrate along the abluminal surface of blood vessels, bypassing the bl...

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Main Authors: Haofeng Huang, Min Zhang, Enyu Huang, Yongfang Zhao, Xiaoyu Li, Pu Qiu, Cairui Li, Jiahua Tao, Yuanqi Zhang, Lianxiang Luo, Guozhu Ning, Ceshi Chen, Jingjing Zhang
Format: Article
Language:English
Published: Springer Nature 2025-06-01
Series:EMBO Molecular Medicine
Subjects:
Breast Cancer
Brain Metastasis
Xenografted Model
LRP8
Reelin
Online Access:https://doi.org/10.1038/s44321-025-00260-0
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Summary:Abstract Brain metastasis (BM) remains a significant challenge in breast cancer (BC) management. While conventional metastatic routes primarily involve hematogenous dissemination, emerging evidence suggests that BC cells can also migrate along the abluminal surface of blood vessels, bypassing the blood-brain barrier (BBB). To investigate this phenomenon, we established a zebrafish xenograft model utilizing GFP-labeled MDA-MB-231 cells, allowing real-time observation of BC cell migration along the posterior cerebral veins. Our findings revealed that LRP8, an apolipoprotein E receptor, is upregulated in BC patients with brain metastasis. Functional studies demonstrated that LRP8 knockdown significantly inhibited proliferation, migration, and invasion of triple-negative breast cancer (TNBC) cells both in vitro and in vivo. Mechanistically, LRP8 promotes the activation of CDC42, enhancing filopodia formation and cell motility, a process influenced by the neuronal extracellular matrix protein, Reelin. Furthermore, we demonstrated the therapeutic potential of MEN 10207, a neurokinin-2 receptor antagonist, in inhibiting TNBC cell migration and suppressing BM formation in both zebrafish and mouse models. These findings provide novel insights into the mechanisms underlying extravascular brain dissemination of BC, highlighting the Reelin-LRP8-CDC42 axis as a potential therapeutic target for this devastating complication.
ISSN:1757-4684

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